METHOD FOR SYNTHESIZING PIRFENIDONE
A process for synthesizing pirfenidone from bromobenzene having less than about 0.15% by weight dibromobenze is disclosed. Also disclosed are processes of synthesizing pirfenidone without using ethyl acetate or n-butanol, and pirfenidone having controlled levels of ethyl acetate, n-butanol, di(5-methyl-2-pyridinone)benzenes, and other impurities having specified retention times. Also disclosed are formulated dosage forms including the disclosed pirfenidone.
1 . A method of synthesizing pirfenidone comprising
admixing bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and an organic solvent under conditions sufficient to form pirfenidone,
wherein the bromobenzene comprises less than about 0.15% by weight or molar ratio dibromobenzene.
2 . The method of claim 1 , further comprising washing the pirfenidone with a saline solution.
3 . The method of claim 1 , further comprising extracting the pirfenidone from the organic solvent mixture with an extracting organic solvent.
4 . The method of claim 3 , wherein the extracting organic solvent comprises toluene.
5 . The method of claim 1 , further comprising admixing a base with the bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and organic solvent.
6 . The method of claim 5 , wherein the base comprises a carbonate.
7 . The method of claim 6 , wherein the carbonate comprises potassium carbonate.
8 . The method of claim 1 , wherein the organic solvent comprises dimethyl formamide.
9 . The method of claim 1 , further comprising crystallizing the pirfenidone from a solvent mixture comprising heptanes and toluene to form purified pirfenidone.
10 . The method of claim 9 , further comprising recrystallizing the purified pirfenidone by
dissolving at least a portion of the purified pirfenidone in an acidic aqueous solution at an elevated temperature to form a pirfenidone solution;
adding a base to the pirfenidone solution until the pH is at least about 11 to form a basic pirfenidone solution; and
cooling the basic pirfenidone solution to a temperature below about 20° C. to form recrystallized pirfenidone.
11 . The method of claim 9 , comprising performing the crystallizing in the absence of ethyl acetate and in the absence of butanol.
12 . Pirfenidone prepared by a method comprising
admixing bromobenzene, 5-methyl-2-pyridone, cuprous oxide, and an organic solvent under conditions sufficient to form pirfenidone;
wherein the bromobenzene comprises less than about 0.15% by weight or molar ratio dibromobenzene.
13 . The pirfenidone of claim 12 , wherein the method further comprises crystallizing the pirfenidone from a solvent mixture comprising heptanes and toluene to form purified pirfenidone.
14 . The pirfenidone of claim 13 , wherein the method further comprises recrystallizing the purified pirfenidone by
dissolving at least a portion of the purified pirfenidone in an acidic aqueous solution at an elevated temperature to form a pirfenidone solution;
adding a base to the pirfenidone solution until the pH is at least about 11 for form a basic pirfenidone solution; and
cooling the basic pirfenidone solution to a temperature below about 20° C. to form recrystallized pirfenidone,
wherein the recrystallizing is done in the absence of ethyl acetate and in the absence of butanol.
15 . The recrystallized pirfenidone of claim 12 , having a purity of at least 98% by weight or molar ratio and being essentially free of ethyl acetate and essentially free of butanol.
16 . Pirfenidone having less than about 0.1% by weight or molar ratio of a di(5-methyl-2-pyridinone)benzene impurity.
17 . The pirfenidone of claim 16 , having less than about 0.05% by weight or molar ratio of a di(5-methyl-2-pyridone)benzene impurity.
18 . The pirfenidone of claim 16 , having a purity of at least 98% by weight or molar ratio and being essentially free of ethyl acetate and essentially free of butanol.